Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis

Acyclovir is approved for the treatment of herpes simplex virus (HSV) and v aricella-zoster virus (VZV) infections in children by the intravenous and o ral routes. However, its use by the oral route in children younger than 2 y ears of age is limited due to a lack of pharmacokinetic data. The objective s of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of bo dy weight three times a day for patients younger than 1 month of age or fou r times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obt ained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estima ted glomerular filtration rate, body surface area, and serum creatinine lev el. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability wa s less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this pop ulation. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 1 2 h for HSV but not far VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections , a twofold increase in the dose seems necessary for children older than ag e 3 months.